Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.992
Filtrar
1.
Zhonghua Zhong Liu Za Zhi ; 42(8): 629-634, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867453

RESUMO

Objective: To investigate the effect of esculin on the proliferation of triple negative breast cancer cells and its molecular mechanism. Methods: MDA-MB-231 cells were treated with 28, 56, 112, 225, 450 and 900 µmol/L of esculin for 24, 48 and 72 h, respectively, and the cell viability was detected by cell counting kit 8 (CCK-8) assay. In addition, MDA-MB-231 cells were treated with 0, 225, 450 and 900 µmol/L of esculin for 48 h. And then the changes in cell morphology were observed by inverted microscope. The clone-forming ability was detected by colony formation assay. The mRNA expression levels of FBI-1, p53 and p21 were detected using real-time fluorescence quantitative polymerase chain reaction. The protein expression levels of FBI-1, p53, p21 and Ki67 were detected by western blot. Results: Compared with the blank control group, the cell viability of MDA-MB-231 cells that treated with esculin significantly decreased in a dose-dependent and time-dependent manners. After treatment with esculin, MDA-MB-231 cells shrunk, flattened, adhered poorly to the culture dish and the cell spacing became larger. Meanwhile, shedding and incomplete cells appeared, of which 900 µmol/L of esculin treatment group showed the most dramatic changes. In addition, the colony formation ratios were decreased to (77.18±5.13)%, (65.94±4.98)% and (45.92±3.70)% in the 225, 450 and 900 µmol/L of esculin treatment groups compared with blank control, respectively (P<0.01). Furthermore, the mRNA and protein expressions of FBI-1 increased, while the levels of p53 and p21 mRNA and protein, as well as the protein expression of Ki67 decreased in a concentration-dependent manner (P<0.01). Conclusion: Esculin may regulate cell cycle-related p53-p21 pathway via FBI-1 mediated DNA replication, thus inhibit the proliferation of triple negative breast cancer cells.


Assuntos
Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Esculina/farmacologia , RNA Mensageiro/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias da Mama/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas/patologia
2.
Anticancer Res ; 40(9): 5081-5090, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878796

RESUMO

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited targets for chemotherapy. This study evaluated the inhibitory effects of novel imidazo[2,1-b]oxazole-based rapidly accelerated fibrosarcoma (RAF) inhibitors, KIST0215-1 and KIST0215-2, on epithelial cell transformation and TNBC tumorigenesis. MATERIALS AND METHODS: Immunoblotting, BrdU incorporation assay, reporter gene assay, and soft agar assay analyses were performed. In vivo effects were studied using the BALB/c mouse xenograft model. RESULTS: KIST0215-1 and KIST0215-2 inhibited the RAFs-MEK1/2-ERK1/2 signalling pathway induced by EGF in MDA-MB-231 cells, which inhibited c-fos transcriptional activity and activator protein-1 transactivation activity. KIST0215-1 and KIST0215-2 also prevented neoplastic transformation of JB6 C141 mouse epidermal cells induced by EGF and consistently suppressed the growth of tumours formed by 4T1 cells in BALB/c mice. CONCLUSION: Inhibition of RAF kinases using KIST0215-1 and KIST0215-2 is a promising chemotherapeutic strategy to treat TNBC.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Genes Reporter , Humanos , Imidazóis/química , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 40(10): 5529-5538, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988876

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is a unique subtype that lacks expression of several conventional biomarkers and has a higher incidence of lymph node invasion and distal metastasis among all breast cancers. Anoikis resistance is the fundamental reason behind tumor cells' survival without their attachment to the extracellular matrix and metastasis to distal organs. Therefore, finding novel anti-cancer drugs that can suppress anoikis resistance in cancer cells is critical for patients with TNBC. MATERIALS AND METHODS: Curcumol, a natural compound, was used to assess whether it can inhibit the anoikis resistance and affects cell mortality and motility of IV2-1 TNBC cells. RESULTS: Curcumol suppressed anoikis resistance and inhibited TNBC cell survival in suspension. Additionally, these anti-cancer effects induced by curcumol could be related to the YAP1/Skp2 molecular pathway. CONCLUSION: Curcumol is an effective Skp2-targeted therapy that attenuates anoikis resistance and metastasis in TNBC cells.


Assuntos
MicroRNAs/genética , Proteínas Quinases Associadas a Fase S/genética , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Anoikis/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
4.
Anticancer Res ; 40(10): 5557-5566, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988879

RESUMO

BACKGROUND/AIM: E- and P-cadherin (E-cadh, P-cadh) control tumor cell invasion, metastatic or stemness potential and chemotherapy resistance. The study aimed to assess E- and P-cadherin expression in breast cancer molecular subtypes. MATERIALS AND METHODS: Immunohistochemistry for E-cadh and P-cadh was performed for 97 breast cancer cases. Membrane (M), cytoplasmic (C) or mixed (MC) patterns of E-cadh and P-cadh were considered in our evaluation. RESULTS: E-cadh and P-cadh C pattern was significantly correlated in the HER2 subtype (p=0.031). P-cadh M pattern was highly specific for the HER2 subtype (p=0.002). Only P-cadh C characterized the triple negative breast cancer subtype (p=0.015). For Luminal B/HER2 cases, P-cadh M pattern was strongly coexpressed with the E-cadh MC pattern (p=0.012). Progesterone receptor (PR) expression influenced E-cadh M pattern in the Luminal B/HER2 subtype (p=0.042). CONCLUSION: E- and P-cadherins define distinct subgroups within breast cancer molecular subtypes. Our findings support the inclusion of E- and P-cadherin into breast cancer molecular classification.


Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Caderinas/genética , Neoplasias de Mama Triplo Negativas/genética , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/metabolismo , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/patologia
5.
Medicine (Baltimore) ; 99(31): e21333, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756119

RESUMO

This study aimed to evaluate the imaging findings and prognostic factors after whole-brain radiotherapy in patients with carcinomatous meningitis from breast cancer.A retrospective analysis of imaging data and prognostic factors was performed in patients treated with whole-brain radiotherapy or whole-brain/spine radiotherapy immediately after the first diagnosis of carcinomatous meningitis from breast cancer at our hospital from January 1, 2010 to December 31, 2018. Statistical significance was set at P < .05 (two-tailed).All patients (n = 31) were females with the mean age of 58.0 ±â€Š11.0 years. The breast cancer subtypes were luminal (n = 14, 45.1%), human epidermal growth factor receptor 2 (HER2)-positive (n = 9, 29.0%), and triple-negative (n = 8, 26.0%) breast cancer. Brain metastasis and abnormal contrast enhancement in the sulci were observed in 21 (67.7%) and 24 (80.6%) patients, respectively. The median survival time after cancerous meningitis diagnosis was 62 (range, 6-657) days. Log-rank test showed significant differences in median survival time after cancerous meningitis diagnosis: 18.0 days for subjects treated with 30 Gy in < 10 fractions (n = 7) vs 78.5 days for subjects treated with 30 Gy in ≥10 fractions (n = 24) (P < .01) and 23.0 days for the triple-negative subtype vs 78.5 days for the other subtype (P < .01) groups. Univariate analysis using the Cox regression model showed significant differences in median survival time after cancerous meningitis diagnosis between the group treated with 30 Gy in <10 fractions and the group treated in ≥10 fractions (hazard ratio [HR] 0.08, 95% confidence interval [CI], 0.03-0.26; P < .01), and between the triple-negative subtype and the other subtypes (HR = 5.48; 95% CI, 1.88-16.0; P < .01) groups.Discontinuation of whole-brain radiotherapy and the presence of triple-negative breast cancer were indicators of poor prognosis.


Assuntos
Neoplasias Encefálicas/secundário , Carcinomatose Meníngea/secundário , Neoplasias de Mama Triplo Negativas/mortalidade , Idoso , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Humanos , Imagem por Ressonância Magnética , Carcinomatose Meníngea/diagnóstico por imagem , Carcinomatose Meníngea/radioterapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias de Mama Triplo Negativas/patologia
6.
PLoS One ; 15(8): e0236516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776970

RESUMO

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.


Assuntos
Colágeno/metabolismo , Neoplasias Mamárias Animais/cirurgia , Prognóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Animais , Gatos , Colágeno/genética , Modelos Animais de Doenças , Feminino , Humanos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética
7.
DNA Cell Biol ; 39(10): 1813-1824, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32816580

RESUMO

Triple-negative breast cancer (TNBC) refers to breast cancer without significant expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2. We sought to identify the hub genes and find the potential progression mechanism of TNBC as well as immunotherapeutic targets. First, we screened the overlapped hub genes of Immune and Stromal, and the tumor mutation burden gene sets, as well as the The Cancer Genome Atlas (TCGA)-TNBC data set. Among these hub genes, we performed gene set enrichment analysis (GSEA) and gene set variation analysis analyses to recognize and evaluate the hub genes. Moreover, immune cell infiltration was evaluated by the CIBERSORT algorithm and single-sample GSEA. In addition, the expression and methylation of scavenger receptor class A member 5 (SCARA5) in TNBC were verified by quantitative PCR and methylation-specific PCR. Also, MTT and transwell assays were used to assess the biological function of SCARA5 in TNBC. SCARA5 and CMA1 were listed, and they mainly participated in cancer-related signaling pathways and immune-related signaling pathways. Interestingly, SCARA5 was closely associated with tumor purity and immune cell infiltration. Moreover, we found that SCARA5 was significantly downregulated and hypermethylation was in the promoter of SCARA5 in TNBC tissues. Our study showed the role of SCARA5 in proliferation and migration of TNBC, and suggested that SCARA5 can potentially serve as a candidate immunotherapy target for TNBC.


Assuntos
Biomarcadores Tumorais/genética , Receptores Depuradores Classe A/genética , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Metilação de DNA , Feminino , Redes Reguladoras de Genes , Humanos , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais , Transcriptoma , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
PLoS One ; 15(8): e0237811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833983

RESUMO

BACKGROUND: Epidemiological studies commonly identify the clinical characteristics and survival outcomes of patients with breast cancer at five years. Our study aims to describe the sociodemographic, clinicopathological characteristics and determine the long-term event-free survival (EFS) and overall survival (OS) of a Peruvian population with triple-negative breast cancer. METHODS: We reviewed the medical records of new cases treated at a single institution in the period 2000-2014. The survival analysis included patients with stages I-IV. Survival estimates at 10 years were calculated with the Kaplan-Meier method and compared with the Log-rank test. We further used multivariate Cox regression analysis to calculate prognostic factors of recurrence and mortality. RESULTS: Among the 2007 patients included, the median age at diagnosis was 49 years (19-95 years). Most patients presented histologic grade III (68.7%), tumor stage II (34.2%), and III (51.0%) at diagnosis. Local and distant relapse was present in 31.9 and 51.4% of the patients, respectively. The most frequent sites of metastasis were the lungs (14.5%), followed by bone (9.7%), brain (9.6%), and liver (7.9%). The median follow-up was 153 months. At 3, 5, and 10 years, the EFS of the population was 55%, 49%, and 41%, respectively, while the OS was 64%, 56%, and 47%, respectively. Moreover, an N3 lymph node status was the most important prognostic factor for both disease relapse (HR: 2.54, 95% CI: 2.05-3.15) and mortality (HR: 2.51, 95% CI: 2.01-3.14) at ten years. An older age and higher T staging were associated with a worse OS, while patients who received radiotherapy and adjuvant chemotherapy had better survival rates. CONCLUSION: The sociodemographic features of Peruvian patients with TNBC are similar to those of other populations. However, our population was diagnosed at more advanced clinical stages, and thus, EFS and OS were lower than international reports while prognostic factors were similar to previous studies.


Assuntos
Neoplasias de Mama Triplo Negativas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Peru/epidemiologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia , Adulto Jovem
9.
Proc Natl Acad Sci U S A ; 117(30): 17785-17795, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32651270

RESUMO

Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.


Assuntos
Recombinação Homóloga/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína BRCA1/genética , Proteína BRCA2/genética , Linhagem Celular Tumoral , Biologia Computacional , Metilases de Modificação do DNA/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Anemia de Fanconi/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Modelos Biológicos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fator de Necrose Tumoral alfa/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(30): 17543-17550, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32669433

RESUMO

Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.


Assuntos
Antígenos de Neoplasias/imunologia , Imunomodulação , Ácidos Nucleicos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia , Camundongos , Oligodesoxirribonucleotídeos/imunologia , Oligonucleotídeos/imunologia , Oxirredução , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
11.
Chem Biol Interact ; 329: 109202, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717189

RESUMO

Triple-negative breast cancer (TNBC) is highly metastatic and lacks effective therapeutic targets among several subtypes of breast cancer. Cancer metastasis promotes the malignancy of TNBC and is closely related to the poor prognosis of the TNBC patients. We aim to explore novel agents that effectively inhibit cancer metastasis to treat TNBC. In our study, 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a CA-4 analogue, could inhibit cell motility and invasion in MDA-MB-231 cells, and the mechanism is closely associated to the inhibition of epithelial-to-mesenchymal transition (EMT). Meanwhile, SQ significantly inhibited the expression and secretion of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells. Moreover, the conditioned medium from SQ-treated MDA-MB-231 cells significantly inhibited the motility and invasion of human umbilical vein endothelial cells (HUVECs), which was correlated with the inhibition of EMT process in HUVECs. In addition, exogenous application of VEGF reversed the occurrence of EMT in HUVECs which stimulated by conditioned medium from SQ-treated cells. Furthermore, SQ inhibited vasculogenic mimicry (VM) formation in MDA-MB-231 cells, which was associated with VE-cadherin and EphA2 down-regulation. This study indicates that SQ inhibits MDA-MB-231 cell metastasis through suppressing EMT and VEGF, thereby implicating this compound might be a potential therapeutic agent against metastatic TNBC.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Organosselênicos/química , Fenóis/química , Receptor EphA2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/genética
12.
Nat Commun ; 11(1): 3256, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591500

RESUMO

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.


Assuntos
Proteína BRCA1/deficiência , Carcinogênese/patologia , Receptor Notch1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Alelos , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/metabolismo , Morte Celular , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Elementos de DNA Transponíveis/genética , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , Mitose , Mutação/genética , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética
13.
PLoS One ; 15(6): e0234012, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544183

RESUMO

Understanding progression of breast cancers to invasive ductal carcinoma (IDC) can significantly improve breast cancer treatments. However, it is still difficult to identify genetic signatures and the role of tumor microenvironment to distinguish pathological stages of pre-invasive lesion and IDC. Presence of multiple subtypes of breast cancers makes the assessment more challenging. In this study, an in-vitro microfluidic assay was developed to quantitatively assess the subtype-specific invasion potential of breast cancers. The developed assay is a microfluidic platform in which a ductal structure of epithelial cancer cells is surrounded with a three-dimensional (3D) collagen matrix. In the developed platform, two triple negative cancer subtypes (MDA-MB-231 and SUM-159PT) invaded into the surrounding matrix but the luminal A subtype, MCF-7, did not. Among invasive subtypes, SUM-159PT cells showed significantly higher invasion and degradation of the surrounding matrix than MDA-MB-231. Interestingly, the cells cultured on the platform expressed higher levels of CD24 than in their conventional 2D cultures. This microfluidic platform may be a useful tool to characterize and predict invasive potential of breast cancer subtypes or patient-derived cells.


Assuntos
Carcinoma Ductal de Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Antígeno CD24/metabolismo , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Microfluídica/métodos , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/genética
14.
PLoS One ; 15(6): e0235343, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584896

RESUMO

Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 2,500 unique superenhancers acquired by tumor cells but absent from normal breast tissue. To identify potential actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFß pseudo-receptor BAMBI.


Assuntos
Elementos Facilitadores Genéticos/genética , Oncogenes/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Guia/metabolismo , Neoplasias de Mama Triplo Negativas/genética
16.
Toxicol Appl Pharmacol ; 401: 115092, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512068

RESUMO

Inflammatory breast cancer (IBC) is a highly metastatic and lethal breast cancer. As many as 25-30% of IBCs are triple negative (TN) and associated with low survival rates and poor prognosis. We found that the microenvironment of IBC is characterized by high infiltration of tumor associated macrophages (TAMs) and by over-expression of the cysteine protease cathepsin B (CTSB). TAMs in IBC secrete high levels of the cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC patients. Herein, we tested the roles of IL-8 and MCP-1/CCL2 in modulating proteolytic activity and invasiveness of TN-non-IBC as compared to TN-IBC and addressed the underlying molecular mechanism(s) for both cytokines. Quantitative real time PCR results showed that IL-8 and MCP-1/CCL2 were significantly overexpressed in tissues of TN-IBCs. IL-8 and MCP-1/CCL2 induced CTSB expression and activity of the p-Src and p-Erk1/2 signaling pathways relevant for invasion and metastasis in TN-non-IBC, HCC70 cells and TN-IBC, SUM149 cells. Dasatinib, an inhibitor of p-Src, and U0126, an inhibitor of p-Erk1/2, down-regulated invasion and expression of CTSB by HCC70 and SUM149 cells, a mechanism that is reversed by IL-8 and MCP-1/CCL2. Our study shows that targeting the cytokines IL-8 and MCP-1/CCL2 and associated signaling molecules may represent a promising therapeutic strategy in TN-IBC patients.


Assuntos
Quimiocina CCL2/biossíntese , Genes src/fisiologia , Neoplasias Inflamatórias Mamárias/metabolismo , Interleucina-8/biossíntese , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Feminino , Genes src/efeitos dos fármacos , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pessoa de Meia-Idade , Proteólise/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
17.
Anticancer Res ; 40(5): 2475-2479, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366391

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Camundongos , Paclitaxel/farmacologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Anticancer Res ; 40(5): 2481-2485, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366392

RESUMO

BACKGROUND/AIM: In the present study, the breast cancer patient-derived orthotopic xenograft (PDOX) model was used to identify an effective drug for a highly aggressive triple negative breast cancer (TNBC). MATERIALS AND METHODS: The TNBC tumor from a patient was implanted in the right 4th inguinal mammary fat pad of nude mice to establish a PDOX model. Three weeks later, 19 mice were randomized into the untreated-control group (n=10) and the eribulin treatment group (n=9, eribulin, 0.3 mg/kg, i.p., day 1). RESULTS: On day 8, eribulin significantly inhibited tumor volume compared to the control group (p<0.01). Eribulin regressed tumors in 3 mice (33.3%) and apparently eradicated them in 6 mice (66.7%). At day 14, tumor regrowth was observed in 2 mice of the eribulin group, which was undetectable on day 8. However, 44.4% (4 out of 9) of the mice in the eribulin group were tumor-free on day 14. CONCLUSION: A single low-dose eribulin was efficacious on a highly aggressive TNBC. The breast cancer PDOX model can be used to identify highly effective drugs for TNBC.


Assuntos
Antineoplásicos/administração & dosagem , Furanos/administração & dosagem , Cetonas/administração & dosagem , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Histocitoquímica , Humanos , Camundongos , Metástase Neoplásica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Anticancer Res ; 40(5): 2509-2514, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366395

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. RESULTS: The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). CONCLUSION: Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.


Assuntos
Bevacizumab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Vinorelbina/farmacologia , Adulto , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 40(5): 2871-2880, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366437

RESUMO

BACKGROUND/AIM: This study aimed to improve the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs). PATIENTS AND METHODS: In this retrospective study, NLR and TIL data from 677 operated breast cancer patients were analysed. The cut-off value of NLR was set at 2.72, and TIL levels were classified as low (<10%), intermediate (≥10 to <50%), and high (≥50%). RESULTS: Recurrence-free survival (RFS) was significantly longer in patients with low NLR (n=459) than in those with high NLR (n=218) (p=0.0383). In ER-positive/HER2-negative and TIL-low breast cancers, there were significant associations between NLR levels and RFS (p=0.0129) or overall survival (OS) (p=0.0046). On multivariate analysis, NLR was a significant and independent factor for OS (hazard ratio=3.78; 95% confidence interval=1.21-14.17; p=0.022). CONCLUSION: These data may be useful for predicting patient prognosis and understanding the clinical significance of immune status in breast cancers.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Feminino , Humanos , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA